PROJECT SUMMARY/ABSTRACT Half of all dementia patients have evidence of vascular contributions to cognitive impairment and dementia (VCID), either as a single pathology or as a mixed dementia. Diabetic women have a 2.3-fold greater risk to develop VCID than non-diabetic women. However, even though prediabetes causes cognitive deficits and is 3 times more common than diabetes, little is known regarding the effects of prediabetes on VCID. Further, why metabolic disease is a larger risk factor for VCID in women than in men is unknown. Women are unique in that they go through menopause. Menopause accelerates mid-life risk factors for dementia, by increasing risk for cardiovascular and metabolic diseases. Despite the fact that nearly all women with VCID are post-menopausal, the influence of menopause on VCID is a critical gap in knowledge. The objective of this proposal is to understand the important interaction between menopause and prediabetes on VCID pathology and identify a novel therapeutic approach to treat VCID in post-menopausal females. Our preliminary data in a mouse model of VCID demonstrate that prediabetes reduces blood flow and accelerates cognitive deficits in peri- menopausal females, the underlying mechanism is unknown but may be related to neuroinflammation or vascular damage; effects in post-menopausal females have not been assessed. In post-menopausal women, the major source of estrogen is local synthesis of 17-? estradiol by the enzyme aromatase in a variety of tissues. Brain aromatase and brain estradiol levels are drastically decreased in women with other forms of dementia, however, the role of aromatase in VCID has yet to be explored. We have discovered that inhibition of aromatase severely impairs cerebrovascular function in female mice suggesting that targeting aromatase in females may be an effective strategy for increasing blood flow to the brain, thereby reducing VCID pathology. We hypothesize that cerebral hypoperfusion, cognitive deficits, and neuroinflammation induced by prediabetes will be exacerbated in post-menopausal females and will be reversed by increasing production of brain-derived estradiol. In Aim 1, using a mouse model of VCID, we will determine if menopause exacerbates cerebral hypoperfusion, neuroinflammation, and cognitive deficits induced by prediabetes. In Aim 2, we will determine if loss of endothelial or astrocytic aromatase causes cerebral hypoperfusion and exacerbates cognitive deficits and neuroinflammation in post-menopausal female mice. In Aim 3, we will determine if increasing estradiol specifically in the brain improves vascular function and reduces cognitive deficits and neuroinflammation in prediabetic post-menopausal female mice. We anticipate these studies will provide mechanistic insight that will facilitate future interventions to decrease the burden of dementia by identifying a novel approach to treat VCID in post-menopausal females: enhancement of brain estradiol. Without knowledge of the effects of menopause on VCID in prediabetic females, development of therapies to treat this high-risk population remains unlikely.